The prevalence of lymphoma in the cat has been reported to be 50 to 200 per 100,000, which is the highest known risk among all animals, and lymphoma is the cause of almost one third of all feline neoplasms.

Andrew Sparkes, head of the Feline Unit at the AHT, reports

THE REASON FOR such a high prevalence of lymphoma in the cat is not well understood, but in part is likely to be due to the association with feline leukaemia virus (FeLV) infection. There is no doubt that infection with this virus is one important cause of feline lymphoma, however, even with better control of FeLV infection (through routine testing and vaccination) lymphoma still remains the most common cancer of cats. Therefore, although FeLV is one important cause, it is not the only factor in the development of lymphoma in cats.

Generally, compared to an uninfected cat, a cat with persistent FeLV infection has approximately 60 times higher risk of developing lymphoma , and the risk in a cat infected with feline immunodeficiency virus (FIV) is some 6 times higher. While FIV may occasionally be a direct be the cause of some lymphomas, it probably more commonly permits tumour development as a manifestation of immunosuppression and compromised early clearing of neoplastically-transformed cells. Generally lymphoma induced by infection with FeLV tends to occur in younger cats, whereas lymphoma unrelated to FeLV is more common in older cats.

Anatomical classification

Various anatomical classification systems have been used for lymphoma in the cat, but most commonly the tumours are divided into mediastinal, alimentary, multicentric, and miscellaneous (extra-nodal) sites.

Mediastinal (thymic) lymphoma

This includes lymphoma of both the thymus and anterior mediastinal lymph nodes – these structures are in the anterior thorax (in front of the heart). The vast majority of these tumours are T-cell lymphomas. There is frequently an associated pleural effusion with clinical signs relating to either dyspnoea or regurgitation or both. With expansion of the mass, there is loss of anterior `rib spring' or manual compressibility of the anterior thorax. The average age of cats with mediastinal lymphoma is around 2 years old, and the Siamese breed appears over-represented with this form of lymphoma. Sometimes mediastinal lymphoma occurs in association with lymphoma at other sites, but in these situations the lymphoma is usually classified as multicentric.

Alimentary lymphoma

Alimentary lymphoma typically occurs in cats 6-9 years of age. The tumour may be focal (one or more large masses) or diffuse (generalized thickening of the intestine). There may be involvement of mesenteric lymph nodes and/or (less commonly) the kidneys, liver and spleen. Most classify alimentary lymphomas as those affecting the GI tract +/- mesenteric lymph nodes – more widespread involvement is often classified as multicentric disease.

Clinical signs generally relate to GI tract obstruction (vomiting or diarrhoea) or malabsorption (weight loss, inappetence, diarrhoea). GI lymphoma may occur in any segment of the intestine (stomach, small intestine or colon) and focal disease may involve a single mass or multiple masses. Clinical examination often reveals palpable abdominal masses and/or lymphadenomegaly. However, diffuse alimentary lymphoma represents a greater diagnostic challenge, and these cases may be difficult to distinguish from severe inflammatory bowel disease.

Multicentric lymphoma

Cats with multicentric lymphoma have tumours at more than one lymphoid site. There may be generalised peripheral and visceral lymphadenomegaly, but concommitant involvement of internal organs is not uncommon. Multicentric lymphomas are most commonly seen in cats 3 to 5 years of age. Some cats will also be leukaemic. Clinical signs with this form of disease vary, but include peripheral lymphadenomegaly, anorexia, weight loss and possibly signs relating to involvement of other sites (liver disease, renal failure, thoracic mass etc.).

Extranodal/miscellaneous lymphoma

Miscellaneous forms of lymphoma are not uncommon, and this type encompasses localised forms of lymphoma where the tumour does not involve the GI, haemopoietic or lymphoid tissues. Areas most commonly affected include the central nervous system, kidneys, skin, and nasal cavity. Sometimes there may be tumours at more than one site, and an association has been noted between the development of renal and nasal lymphoma in some cats. Clinical signs relate to the site of the primary tumour, the average age of affected cats is 5 to 9 years.

Staging of lymphoma

Clinical staging of lymphoma is usually undertaken using the WHO Clinical Staging for Tumours of Domestic Animals system:

Each stage is also subclassified into:

a Without systemic signs

b With systemic signs

Diagnosis of lymphoma

Definitive diagnosis of lymphoma is based on cytological or histological examination of tissue samples. Abnormalities in serum biochemistry are not common in feline lymphoma cases, although paraneoplastic hypercalcaemia is occasionally seen, and specific organ involvement (eg, liver, kidney) may lead to biochemical changes reflecting organ dysfunction.

Various haematological changes can be seen in lymphoma cases. Anaemia is commonly seen, but occurs much more frequently in FeLV-positive than FeLV-negative cats (68 per cent vs 9 per cent in one study). Leucocytosis and lymphopenia are also relatively common findings and less commonly there may be leucopenia, thrombocytopenia and pancytopenia. Atypical lymphocytes may be found in the circulation and may arise in three situations — they may reflect primary lymphoid leukaemia (which in later stages may result in haematogenous metastases); they may reflect bone marrow infiltration in lymphoma cases with subsequent production of circulating neoplastic lymphocytes; or they may arise form shedding of tumour cells from solid neoplasms into adjacent blood vessels.

Evaluation of lymphoma cases should always include FeLV and FIV testing, and for proper staging of the tumour evaluation of bone marrow aspirates or biopsies is required. However, as this may not necessarily affect either prognosis or therapy the necessity for this on a routine basis is questionable.

Therapy of lymphoma

A vast array of different protocols have been described for the chemotherapy of feline lymphoma, with few published studies critically appraising the proposed benefits of one protocol over another. Partly for this reason, treatment using two or three simple, well-proven protocols is often recommneded. Unless well-documented evidence suggests otherwise, it is also helpful to the clinician to use protocols with which they are familiar as this will help in anticipation and recognition of side-effects associated with therapy as well as routine monitoring of the case.

COP/COAP protocol

The traditional COP protocol (cyclophosphamide, vincristine - `Oncovin', and prednisolone) is the one most commonly employed treatments for feline lymphoma and was initially reported in the early 1980's. Variations of this protocol have also been reported, and a regime in common use is:

Induction therapy

1   Vincristine: 0.5-0.75mg/m 2 IV weekly.

2   Cyclophosphamide: 50mg/m 2 orally every other day. However, tablets should not be broken, and therefore the weekly dose of cyclophosphamide is calculated at a dose rate of 150mg/m 2 . This weekly dose is then divided by 25mg or 50mg (according to the tablet size available) and the frequency of dosing calculated. Most cats require one 50mg tablet every 7-10 days.

3   P rednisolone: 40mg/m 2 orally, daily for the first 7 days then reducing to 20mg/m 2 orally every other day.

Induction therapy is usually continued for a minimum of six weeks, but can be prolonged if the tumour is not in remission and significant side-effects have not occurred.

For CNS lymphoma, addition of cytosine arabinoside at 100mg/m 2 subcutaneously for the first two clays of induction therapy has been recommended due to the good penetration of this drug across the blood-brain barrier.

Studies have suggested that the addition of L-asparaginase or methotrexate to the standard COP protocol carries no additional benefit.

Maintenance therapy

As above, but the vincristine is given at 0.5-0.75mg/m 2 IV at 3-4 weekly intervals.

Alternative maintenance therapy

For owners who find the vincristine injections difficult, or for cats that develop severe myelosuppression (usually related to cyclophosphamide therapy), an alternative oral (‘LMP') maintenance protocol is:

1    Chlorambucil ('Leukeran'): 2mg/m 2 orally every other day (or 20mg/m 2 every 14 days). Higher doses (2mg per cat every other day) have also been suggested, and appear to be safe in the cat.

2    Methotraxate: 2.5-5.0mg/m 2 orally twice times weekly.

3    Prednisolone: 20mg/m 2 orally every other day.

Duration of maintenance therapy

Assuming there is no relapse, the duration of maintenance therapy is controversial. Some authors recommend continual maintenance therapy for the remainder of the animal's life, whereas other recommend maintenance is continued for as little as 1 year. Generally, if complete remission is maintained, we continue with maintenance therapy for 2 to 3 years.

Converting bodyweight (kg) to body surface area (m2)

Side-effects with COP

We generally find that cats tolerate COP therapy very well. Side-effects can however occur, and while the myelosuppressive potential of vincristine is moderate, that of cyclophosphamide is more potent. The nadir in neutrophil counts usually occurs around 7 days after cyclophosphamide therapy. If neutrophil counts fall below 1.0x 10 9 /1, therapy should be temporarily stopped (for 3-7 days) and re-instituted at a lower dose (eg, 25 per cent reduction) when neutrophil counts have recovered. Fine-tuning of cyclophosphamide therapy in cats is hampered by the tablet size available though (and the tablets should not be broken), and if reducing the frequency of dosing does not overcome myelosuppression, alternative protocols should be used. Haematology should ideally be performed on a weekly basis during the induction phase, and perhaps every 3 to 4 weeks thereafter. Haemorrhagic cystitis is a very uncommon side-effect of cyclophosphamide therapy in cats.

Anorexia, vomiting and occasionally diarrhoea may be seen in association with vincristine or cyclophosphamide therapy. Supportive therapy may be required, and temporary cessation of therapy or reduction in the dose used. Antiemetics should be used where nausea or vomiting occurs, and cyproheptadine (4-8 mg bid) can be valuable as an appetite stimulant.

Analgesic therapy should not be overlooked as an important part of the management of the cancer patient — frequently lymphoma may be associated with pain and this should be managed appropriately, although non-steroidal anti-inflammatory drugs should be avoided if the cat is receiving corticosteroids.

Use of doxorubicin

Doxorubicin is another drug that has been evaluated for treatment of feline lymphoma. While it does not appear to be an effective agent for induction therapy in the cat, it has been reported to be useful as a maintenance agent. In one study, following COP induction, it proved to be an effective alternative to maintenance COP when used for this as a single agent given at 25mg/m 2 IV every three weeks for 6 months. Therapy for longer than this is not recommended due to the possibility of cumulative cardiotoxicity with doxorubicin. Many clinicians do not use doxorubicin as a ‘first choice' treatment for lymphoma in cats, but its use may be appropriate in cats that have come out of remission.

Prognosis

Studies have consistently failed to show an association between clinical stage of lymphoma or histological grade and response to therapy. Indeed, the two most reliable guides to response are the clinical condition of the cat at the start of therapy, and the initial response to therapy. The latter is particularly helpful, and in our experience many owners are keen to try chemotherapy for 1 to 2 weeks to allow response to be evaluated before making a long-term decision about therapy.

Complete remission is typically achieved in 40-60 per cent of feline lymphoma cases with median survival times ranging from 2 to 12 months. Although there is some variation between studies, most authors seem to agree that mediastinal and multicentric lymphoma are the most responsive to therapy, while alimentary and renal lymphoma carries a somewhat more guarded prognosis. Nevertheless, even with alimentary lymphoma, prolonged survival (more than a year) is possible and is achieved with some frequency. In one study (Mahony and others 1995, JAVMA 207;1593-1598) 9 of 28 cats with alimentary lymphoma achieved complete remission with COP protocol, and the median survival of these cats was 213 days with 5 cats surviving beyond a year.

Particularly with GI lymphoma, but potentially with other forms too, anorexia and inappetence may be a significant problem. If these cases do not respond to analgesic therapy, and/or anti-emetics, nutritional support should be instituted with, for example, oesophagostomy tube feeding.

Cats that are FeLV positive have a somewhat poorer prognosis than those that are negative, but this effect is not strong, and is certainly not a reason to withhold therapy in an infected cat.

Once recurrence occurs, although rescue protocols have been described and can be used, it appears to be very difficult to achieve reversal and induce remission for a second time.